There is increasing evidence that intermittent hypoxia enhances cardiac resistance to ischemic stress. Recently, we demonstrated remarkable protection of canine myocardium by a 20 day program of 5-10 min normobaric hypoxia, with intervening 4 min periods of normoxia, totaling 25-70 min of hypoxia per day. In 17 non-hypoxic dogs, 39 [unreadable] 4% of ischemic myocardium infarcted during a 1 hour coronary occlusion/5 hour reperfusion protocol, and 82% of the dogs developed ventricular tachycardia and/or fibrillation. In 9 hypoxia conditioned dogs, only 1.1 [unreadable] 0.3% of ischemic myocardium infarcted, and no ventricular tachycardia or fibrillation occurred. Collateral blood flow to ischemic myocardium and arterial hematocrit and O2 content were similar in both groups. These remarkable results suggest that adaptation to intermittent normobaric hypoxia could provide a safe, powerful and practical treatment complementary to conventional pharmaceutical and surgical interventions to protect myocardium from impending ischemia. However, rigorous preclinical studies of this phenomenon, particularly in large mammals, are essential to implement hypoxia conditioning as a novel modality to prevent cardiac injury in clinical settings. The global objective of the proposed investigation is to address three important questions regarding the practical application and mechanism of intermittent hypoxia conditioning: 1) How long does the cardioprotection persist after the conditioning program is interrupted? 2) How effective is hypoxia conditioning at preventing myocardial injury inflicted by protracted coronary occlusions exceeding 1 hour? 3) Does oxidative stress, produced in myocardium by cyclic hypoxia-reoxygenation, evoke cardioprotective adaptations? To address these questions, hypoxia-conditioned and non-hypoxic control dogs will be subjected to occlusion and reperfusion of the left anterior descending coronary artery, while ventricular arrhythmias are monitored. Myocardial infarct size, ischemic myocardium at risk, and collateral blood flow will be measured to quantify ischemic injury. Information on hypoxia-evoked cardioprotection resulting from this investigation will provide the crucial foundation for future clinical exploitation of this powerful phenomenon. Myocardial ischemia and its sequelae are the leading causes of death and disability in the United States, yet few noninvasive interventions are available to prevent ischemic damage to the myocardium. The applicants have demonstrated that a program of brief, intermittent, normobaric hypoxia produces remarkable protection against ischemia- induced myocardial infarction and lethal arrhythmias. Information on hypoxia-evoked cardioprotection resulting from this investigation will establish an empirical foundation to support eventual clinical application of this powerful cardioprotective phenomenon. [unreadable] [unreadable] [unreadable]